1. Field of the Invention
This invention is related to naphthyl-substituted .alpha.-amino acid derivatives that are active as excitatory amino acid receptor antagonists acting at glutamate receptors, specifically N-methyl-D-aspartate ("NMDA") receptors. The invention also relates to the use of those .alpha.-amino acid derivatives as neuroprotective agents for treating cerebral ischemia caused by cerebral trauma, stroke, hypoglycemia, heart attack and surgery; as a treatment for anxiety and schizophrenia; as an analgesic and adjunct to opioid analgesia therapy; and to treat chronic neurodegenerative disorders such as Huntington's Disease, ALS, Parkinsonism, and Alzheimer's Disease.
2. Related Background Art
Various .alpha.-amino acid derivatives, such as phenylalanine derivatives, have been disclosed as NMDA receptor antagonists. U.S. Pat. No. 5,175,153 discloses 3-(phosphonomethyl)phenylalanine as an NMDA receptor antagonist and generically discloses compounds of the formula ##STR1## wherein: n is 0, 1, or 2; R.sup.1, R.sup.2 and R.sup.5 are independently hydrogen or a pharmaceutically acceptable labile ester or amide residue; R.sup.3 and R.sup.4 are independently hydrogen, hydroxy, lower alkyl optionally substituted by hydroxy or methoxy, aryl, aralkyl, lower alkoxy, R.sup.10 S(O).sub.0-1 (CH.sub.2).sub.q wherein q is 0, 1, or 2 and R.sup.10 is lower alkyl, halogen, trifluoromethyl, or R.sup.3 and R.sup.4 when on adjacent ring carbons are together --CH.dbd.CH--CH.dbd.CH--; R.sup.9 is a hydrogen or a protective group; Q is --(CH.sub.2).sub.m --, --(CH.dbd.CH)--, --CH.sub.2 --(CH.dbd.CH)--, or --(CH.dbd.CH)--CH.sub.2 -- wherein m is 0, 1, 2 or 3. This reference does not disclose the naphthyl-substituted .alpha.-amino acid derivatives of the present invention or their unexpectedly improved NMDA receptor antagonism.
Phenylalanine derivatives having a phenyl or substituted phenyl group attached to C-1 of the primary phenyl ring are disclosed in U.S. Pat. No. 5,162,311. [See also, Mueller, et al., Helv. Chim. Acta, 75(3), 855-64 (1992)]. This patent specifically discloses (+)-.alpha.-amino-3-(5-phosphonomethyl-[1,1'-biphenyl]-3-yl)propanoic acid. The claims of U.S. Pat. No. 5,162,311 are, however, specifically limited to an unsubstituted or monosubstituted phenyl ring and, thus, do not suggest naphthyl-substituted phenylalanine derivatives.
U.S. Pat. No. 4,918,064 discloses phenylglycine analogs that may be aryl substituted. However, naphthyl substituents are not exemplified, and the phenyl ring is specifically substituted at C-4 instead of C-3.
None of the aforementioned references disclose or suggest the unexpected improvement in NMDA receptor antagonist activity of the naphthyl-substituted .alpha.-amino acid derivatives of this invention, or the discovery that the compounds of this invention are substrates to a neutral amino acid transporter which may enhance their access into the central nervous system.
It is particularly evident from the literature that most potent NMDA receptor antagonists have an unnatural (R)-configuration of the .alpha.-amino acid moiety. Amino acids with an unnatural (R) configuration are neither able to utilize neutral amino acid transport systems for absorption systemically, nor can they utilize transport systems in endothelial cells of the blood brain barrier to enhance their transport into the central nervous system (CNS). The naphthyl-substituted .alpha.-amino acid derivatives of this invention were designed specifically to enhance their access into the CNS via neutral amino acid transport systems. Without being held or bound to any theory, it is believed that the naphthyl-substituted .alpha.-amino acid derivatives of the present invention act as transport substrates, which may help to explain their unexpected in vivo potency.
Among excitatory amino acid receptor antagonists recognized for usefulness in the treatment of disorders are those that block NMDA receptors. NMDA receptors are intimately involved in the phenomenon of excitotoxicity, which may be a critical determinant of outcome of several neurological disorders. Disorders known to be responsive to blockade of the NMDA receptor include acute cerebral ischemia (stroke or cerebral trauma, for example), muscular spasm, convulsive disorders, neuropathic pain and anxiety, and may be a significant causal factor in chronic neurodegenerative disorders such as Parkinson's disease [T. Klockgether, L. Turski, Ann. Neurol. 34, 585-593 (1993)], human immunodeficiency virus (HIV) related neuronal injury, amyotrophic lateral sclerosis (ALS), Alzheimer's disease [P. T. Francis, N. R. Sims, A. W. Procter, D. M. Bowen, J. Neurochem. 60 (5), 1589-1604 (1993)] and Huntington's disease. [See S. Lipton, TINS 16 (12), 527-532 (1993); S. A. Lipton, P. A. Rosenberg, New Eng. J. Med. 330 (9), 613-622 (1994); and C. F. Bigge, Biochem. Pharmacol. 45, 1547-1561 (1993) and references cited therein.]. NMDA receptor antagonists may also be used to prevent tolerance to opiate analgesia or to help control withdrawal symptoms from addictive drugs (Eur. Pat. Appl. 488,959A). A recent review describes most of the recent structural types of NMDA receptor antagonists [C. F. Bigge and T. C. Malone, Curr. Opin. Ther. Pat., 951-989 (1993)].
An object of this invention is to provide novel naphthyl-substituted .alpha.-amino acid derivatives which are unexpectedly potent NMDA antagonists. The improved potency of these compounds advantageously allows for the administration of lower doses of the compounds which may result in the reduction of side effects associated with NMDA antagonist therapy.
A further object of this invention is to provide a pharmaceutical composition containing an effective amount of the naphthyl-substituted .alpha.-amino acid derivatives to treat cerebrovascular disorders responsive to blocking glutamate and NMDA receptors, and a pharmaceutically acceptable carrier.
Another object of this invention is to provide a method of treating disorders responsive to the antagonism of glutamate or aspartate receptors in a human by administering a pharmaceutically effective amount of the naphthyl-substituted .alpha.-amino acid derivatives of this invention.
A further object of this invention is directed to novel intermediates of the napthyl-substituted .alpha.-amino acid derivaties of this invention.